Catheter devices and methods for their use in the treatment of calcified vascular occlusions

ABSTRACT

Catheter devices and methods for their use in enhancing fluid flow through a vascular site occupied by a vascular occlusion are provided. The subject catheter devices include at least a first, second and third lumen, where: (a) the first lumen is used for delivery of an acidic dissolution solution to the vascular site; (b) the second lumen is used for delivery of a buffer solution to the vascular site; and (c) the third lumen is used for removal of fluid from the vascular site. In many preferred embodiments, the first, second and third lumens are coaxial. In practicing the subject methods, the vascular site is flushed simultaneously with an acidic dissolution fluid and a buffer solution, where flushing is carried out in a manner such that only a surface of the vascular occlusion is contacted with the acidic dissolution fluid and the remainder of the vascular site is not contacted with fluid having a pH that is lower than about 4. Flushing is carried out in this manner for a period of time sufficient for fluid flow through the vascular site to be enhanced, e.g. increased or established. The subject catheter devices and methods find use in the treatment of a variety of different vascular diseases characterized by the presence of calcified vascular occlusions, including peripheral and coronary vascular diseases.

CROSS-REFERENCE

This application is a continuation of Ser. No. 09/425,826, filed Oct.22, 1999 now U.S. Pat. No. 6,290,689, which is incorporated herein byreference in its entirety and to which application we claim priorityunder 35 USC § 120.

INTRODUCTION

1. Technical Field

The field of this invention is vascular disease, particularly vasculardiseases characterized by the presence of calcified vascular occlusions.

2. Background of the Invention

Vascular occlusions, which may be partial or total occlusions, play aprominent role in many types of vascular disease. Many vascularocclusions encountered in the treatment of vascular disease arecharacterized by having a mineral component, i.e. they are calcified.Calcified vascular occlusions, both partial and total, are found in bothperipheral and coronary vascular disease A variety of differentprotocols have been developed for treating vascular diseasescharacterized by the presence of partial or total occlusions. Suchtreatment methodologies generally involve mechanical removal orreduction of the size of the occlusion, and include: bypass surgery,balloon angioplasty, mechanical debridement, atherectomy, and the like.

Despite the plethora of different treatment strategies that have beendeveloped for the treatment of vascular diseases associated withvascular occlusions, there are disadvantages associated with eachtechnique, such as tissue damage, invasiveness, etc. For example,restenosis is a common complication that results in arteries in whichocclusions have been mechanically removed.

Calcified vascular occlusions pose significant challenges to currentlyemployed treatment methodologies. For example, where the target vascularocclusion is a total occlusion, it is difficult if not impossible topass a guidewire through the occlusion, which step is required for manyof the currently used procedures. While bypass grafts are sometimesavailable as alternatives in such instances, bypass procedures havetheir own risks and complications. Furthermore, if there is noappropriate anastomosis site available, amputation is often the onlyalternative.

As such, there is continued interest in the development of endovascularmethods of treating vascular occlusions. Of particular interest would bethe development of methods and devices suitable for use in the treatmentof calcified vascular occlusions.

Relevant Literature

U.S. patents of interest include: U.S. Pat. Nos. 4,445,892; 4,573,966;4,610,662; 4,636,195; 4,655,746; 4,690,672; 4,824,436; 4,911,163;4,976,733; 5,059,178; 5,090,960; 5,167,628; 5,195,955; 5,222,941;5,370,609; 5,380,284; 5,443,446; 5,462,529; 5,496,267; 5,785,675; and5,833,650. See also: Koltun et al., Arch. Surg. (August 1987)122:901-905; Olin et al., Ann. Emerg. Med. (November 1988) 17:1210-1215;Hargrove et al., Surgery (December 1982) 92:981-993; and Rickard et al.,Cardiovascular Surg. (December 1997) 5:634-640. See also PERIPHERALENDOVASCULAR INTERVENTIONS, 2^(nd) ed. (White & Fogarty eds., Springer,N.Y.)(1996) pp 565-576.

SUMMARY OF THE INVENTION

Multi-lumen catheter devices and methods for their use in enhancingfluid flow through a vascular site occupied by a vascular occlusion areprovided. The subject catheter devices include at least a first, secondand third lumen, where: (a) the first lumen is used for delivery of anacidic dissolution solution to the vascular site; (b) the second lumenis used for delivery of a buffer solution to the vascular site; and (c)the third lumen is used for removal of fluid from the vascular site. Inmany preferred embodiments, the first, second and third lumens arecoaxial. In practicing the subject methods, the vascular site is flushedsimultaneously with an acidic dissolution fluid and a buffer solution,where flushing is carried out in a manner such that only a surface ofthe vascular occlusion is contacted with the acidic dissolution fluidand the remainder of the vascular site is not contacted with fluidhaving a pH that is lower than about 4. Flushing is carried out in thismanner for a period of time sufficient for fluid flow through thevascular site to be enhanced, e.g. increased or established. Alsoprovided are systems and kits comprising the subject catheter devices.The subject catheter devices, kits, systems and methods find use in thetreatment of a variety of different vascular diseases characterized bythe presence of calcified vascular occlusions, including peripheral andcoronary vascular diseases.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A & 1B provide views of a totally occluded and partially occludedvascular site, respectively.

FIG. 2A provides a representation of an aspiration catheter according ofan embodiment of the subject invention while

FIG. 2B provides a representation of a total occlusion catheter insertfor use in the aspiration catheter of FIG. 2A.

FIG. 3 provides a representation of a partial occlusion catheter insertfor use in the aspiration catheter of FIG. 2A.

FIG. 4 provides a depiction of the use of the partial occlusion cathetersystem according to the subject invention.

FIG. 5 provides a representation of a system according to the subjectinvention, which system includes a catheter device, manifold, fluidreservoirs, etc.

FIGS. 6 to 8 provides a representation of the various stages of the useof the total occlusion system of the subject invention.

FIGS. 9 and 10 provide view of alternative embodiments of the subjectmethods in which external energy is applied to the occlusion, e.g. bymovement of a guidewire as shown in FIG. 9.

FIG. 11 illustrates the limited range of the acidic dissolution fluidwhen applied according to the subject methods.

FIG. 12 provides another view of a total occlusion catheter of thecatheter systems of the subject invention.

FIG. 13 provides another view of a partial occlusion catheter of thecatheter systems of the subject invention.

FIG. 14 provides another view of an aspiration or irrigation catheter ofthe catheter systems of the subject invention.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

Multi-lumen catheter devices and methods for their use in enhancingfluid flow through a vascular site occupied by a vascular occlusion areprovided. The subject catheter devices include at least a first, secondand third lumen, where: (a) the first lumen is used for delivery of anacidic dissolution solution to the vascular site; (b) the second lumenis used for delivery of a buffer solution to the vascular site; and (c)the third lumen is used for removal of fluid from the vascular site. Inmany preferred embodiments, the first, second and third lumens arecoaxial. In practicing the subject methods, the vascular site is flushedsimultaneously with an acidic dissolution fluid and a buffer solution,where flushing is carried out in a manner such that only a surface ofthe vascular occlusion is contacted with the acidic dissolution fluidand the remainder of the vascular site is not contacted with fluidhaving a pH that is lower than about 4. Flushing is carried out in thismanner for a period of time sufficient for fluid flow through thevascular site to be enhanced, e.g. increased or established. Alsoprovided are systems and kits comprising the subject catheter devices.The subject catheter devices, kits, systems and methods find use in thetreatment of a variety of different vascular diseases characterized bythe presence of calcified vascular occlusions, including peripheral andcoronary vascular diseases.

Before the subject invention is described further, it is to beunderstood that the invention is not limited to the particularembodiments of the invention described below, as variations of theparticular embodiments may be made and still fall within the scope ofthe appended claims. It is also to be understood that the terminologyemployed is for the purpose of describing particular embodiments, and isnot intended to be limiting. Instead, the scope of the present inventionwill be established by the appended claims.

It must be noted that as used in this specification and the appendedclaims, the singular forms a, an, and the include plural referenceunless the context clearly dictates otherwise. Unless defined otherwiseall technical and scientific terms used herein have the same meaning ascommonly understood to one of ordinary skill in the art to which thisinvention belongs.

Catheter Devices-general Features

As summarized above, the subject invention provides multi-lumen catheterdevices which are designed for enhancement of fluid flow through avascular site that is at least partially, if not totally, occluded by avascular lesion, particularly a vascular calcified lesion. The subjectmulti-lumen catheter devices comprise at least three distinct lumens,i.e. the subject devices at least include a first, second and thirdlumen.

The first lumen is characterized in that it has at least an inner wallthat is resistant to reaction with an acidic dissolution fluid, at leastfor a period of time sufficient for the intended use of the catheter tobe completed. More specifically, at least the inner wall of the catheteris fabricated from a material that is resistant to reaction with asolution having a pH of less than about 4, preferably less than about 2and more preferably less than about 1. As such, it must be inert to asolution that has a pH from about 0 to 4. Generally, the material fromwhich the inner surface of the first lumen is fabricated must beresistant to reaction with an acidic solution, e.g. must besubstantially inert with respect to the acidic dissolution fluid, for aperiod of time that is at least about 10 min long, preferably at leastabout 20 min long and more preferably for at least about 1 hour long orlonger. Materials of interest from which at least the inner surface ofthe first lumen may be fabricated include: biocompatible polymers, e.g.polyimide, PBAX, polyethylene, and the like. The thickness of the innersurface of the first lumen must be sufficient to protect the remainderof the catheter device from any corrosive reaction with the acidicdissolution solution that is conveyed or delivered through the firstlumen during use of the catheter device, as described in greater detailinfra. As such, the thickness of the inner wall is typically at leastabout 0.5 mm, usually at least about 0.1 mm and more usually at leastabout 0.25 mm. The first lumen of the subject multi-lumen catheterdevices is further characterized in that it is capable of being attachedin fluid communication, either directly or indirectly, with an acidicdissolution fluid reservoir. The effective total cross sectional areathrough which acidic dissolution fluid flows during use of the subjectdevices, (i.e. the total cross-sectional areas of any openings presentat the distal end of the first lumen less any area occupied by ablocking element positioned in any of the openings) is sufficient toprovide the requisite rate of flushing of the vascular occlusion withthe acidic dissolution fluid. Generally, the effective total crosssectional area provided by the at least one opening at the distal end ofthe first lumen is at least about 0.1 mm², often at least about 0.2 mm²and somtimes at least about 0.3 mm², where the total effective crosssectional area at the distal end of the first lumen may be as large as0.6 mm² or larger, but in certain embodiments will not exceed about 0.5mm² and in other embodiments will not exceed about 0.4 mm².

The second lumen of the subject catheter device is employed to convey ordeliver a pH elevating fluid, e.g. a buffer, to a vascular site, asdescribed in greater detail infra. As such, the second lumen of thesubject multi-lumen catheter devices is characterized in that it iscapable of being attached in fluid communication, either directly orindirectly, with a pH elevating fluid reservoir. The effective totalcross-sectional area of the opening at the distal end of the secondlumen, where effective total cross-sectional area is as defined above(e.g. the annular space in a coaxial embodiment, as described in greaterdetail infra), is sufficient to provide the requisite amount of pHelevating solution to the vascular site so that any portion of thevascular site apart from the target surface of the vascular solution isnot contacted with a solution which has a pH of less than about 4,preferably less than about 5 and more preferably less than about 6.Accordingly, the effective cross-sectional area of the opening(s) of thedistal end of the second lumen is at least about 0.8 mm², usually atleast about 1.4 mm² and may be as larger as 2.2 mm² or larger, butgenerally does not exceed about 2.0 mm² and usually does not exceedabout 1.5 mm².

The third lumen of the subject multi-lumen catheter devices is anaspiration lumen. The aspiration lumen is characterized by at leasthaving a distal opening(s) with an effective total cross-sectional area(e.g. the area of the annular space in the coaxial embodiments describedinfra) that is sufficiently large to remove fluid, and debris, from thevascular site at substantially the same rate that fluid (e.g. buffersolution and acidic dissolution solution) is introduced into thevascular site during use of the device, such that the fluid pressure inthe vascular site remains substantially isobaric or isometric, where bysubstantially isobaric or isometric is meant that the fluid pressure inthe vascular site does not vary by more than about 50 mm Hg, preferablydoes not vary by more than about 10 mm Hg, and more preferably does notvary by more than about 5 mm Hg over the total flushing period.

The subject catheter devices are further characterized by at leastincluding a first vascular occlusion means positioned at some pointproximal to the distal end of the outer surface of the catheter device,e.g. the outer surface of the aspiration catheter in the coaxialembodiments described infra. By vascular occlusion means is meant anydevice or component that is capable of substantially, and preferablycompletely, occluding a vessel, e.g. an artery or vein. By substantiallyoccluding is meant that fluid, e.g. blood, flow past the occlusion meansupon activation is reduced by at least 95%, usually by at least 97% andmore usually by at least 99%, where in preferred embodiments, fluid flowis reduced by 100% such that the fluid flow into the vascular site issubstantially, if not completely, inhibited. Any convenient means may beemployed, where a vascular occlusion means of particular interestincludes an inflatable balloon. Inflatable balloons are well known inthe catheter art, and any convenient balloon configuration may beemployed. While the inflatable balloon may be one that is designed to beinflated with a gas or liquid, of particular interest in manyembodiments are those that are configured to be inflated with a liquid,e.g. a pH elevating solution as described in greater detail infra.

Catheter Devices—Specific Alternative Embodiments

The subject invention provides a number of distinct alternativeembodiments of the subject catheter devices. One preferred specificembodiment of interest is a coaxial embodiment, in which each of thefirst, second and third lumens are coaxial. Other alternativeembodiments include embodiments in which at least one of the lumens isnot coaxial with the other lumens, as well as embodiments in which noneof the lumens is coaxial. Each of these representative alternativeembodiments is now described in greater detail below.

Coaxial Embodiments

As mentioned above, a preferred embodiment of the subject multi-lumencatheter devices is a coaxial embodiment, in which the first, second andthird lumens of the subject catheter device are coaxial. By “coaxial” ismeant that the first, second and third lumens share a common axis. Assuch, in these embodiments the first lumen is present in an elementpositioned inside the second lumen, which in turn is present in anelement positioned inside the third lumen. Generally, the first, secondand third lumens are found inside fluid delivery means which arepositioned inside one another, where the fluid delivery means are oftenelongated tubular elements. The coaxially positioned fluid deliverymeans comprising the first, second and third lumens, i.e. the first,second and third fluid delivery means, may be held in a staticrelationship with respect to one or another or may be movable withrespect to one another, such that at least one of the fluid deliverymeans, and preferably at least two of the fluid delivery means may bemoved without moving the other fluid delivery means—i.e. each of thefirst, second and third fluid delivery means may be moved independentlyof one another. Spacers or other means on the inner walls of at leastthe second and third lumens may be present to maintain the coaxialconfiguration.

In this coaxial embodiment of the subject invention, one of the lumensserves to deliver an acidic dissolution fluid, one of the lumens servesto deliver a pH elevating fluid and one of the lumens serves to removefluid from the vascular site. In other words, two of the lumens serve tointroduce fluid to the vascular site and one of the lumens serves toremove fluid from the vascular site. While any of the lumens may serveany of the above functions, generally, the first lumen which deliversthe acidic dissolution solution (i.e the one that has at least an innersurface that is substantially inert to the acidic dissolution fluid) isthe innermost lumen of the coaxial lumens of the device. As such, thefirst lumen is the lumen with the inner walls that are closest to thecenter line or axis of the coaxial catheter device.

The first lumen is generally positioned along the center line or axis ofa first elongated fluid delivery means, where the fluid delivery meansgenerally extends along the length of the catheter from its proximal todistal end. The fluid delivery means is typically tubular in shape, andmay have a variety of different cross-sectional configurations,including square, triangular, trapezoidal, circular, elliptical,irregular, and the like, where often the cross-sectional shape of theelongated tubular member is curvilinear, and more often is circular.

The design of the first fluid delivery means may vary depending on thenature of the target vascular occlusion, e.g. whether the targetvascular occlusion is a total occlusion or a partial occlusion. Thetotal occlusion first fluid delivery means, e.g. the total occlusioncatheter insert, is an elongated tubular structure, as described above,having a blunt ended, open distal end through which fluid may be flowedunder pressure. The length of the total occlusion catheter insertgenerally ranges from about 90 to 210 cm, usually from about 100 to 190cm and more usually from about 110 to 150 cm. The outer diameter of thetotal occlusion catheter insert is such that the catheter insert may beslidably positioned in the second lumen (i.e. the lumen of the secondfluid delivery means, as described infra), and typically ranges fromabout 0.4 to 2.0, usually from about 0.4 to 1.6 mm. The inner diameterof the total occlusion catheter insert typically ranges from about 0.2to 1.0, usually from about 0.25 to 1.0 and more usually from about 0.3to 1.0 mm.

Where the target occlusion is a partial occlusion, a partial occlusionfirst fluid delivery means is employed, i.e. a partial occlusioncatheter insert. The partial occlusion catheter insert differs from thetotal occlusion catheter insert in a number of ways. First, the partialocclusion catheter insert includes a balloon or analogous vesselocclusion means at its distal end, where the distance between thevascular occlusion means and the distal end of the catheter inserttypically ranges from 1 to 30 mm, usually from about 10 to 20 mm.Second, the partial occlusion vascular insert has one or more fluidintroduction ports proximal to the proximal side of the distal balloon.The diameter of the infusion ports may vary, but typically ranges fromabout 0.2 to 1.2, usually from about 0.4 to 1.0 and more usually fromabout 0.5 to 0.8 mm. Where the vascular occlusion means on the partialocclusion catheter insert is a balloon, a balloon inflation lumen isalso present in the partial occlusion catheter insert. Finally, the endof the partial occlusion catheter insert is sealed. The length of thepartial occlusion catheter insert generally ranges from about 90 to 250cm, usually from about 100 to 230 cm and more usually from about 110 to190 cm. The outer diameter of the partial occlusion catheter insert issuch that the catheter insert may be slidably positioned in the secondlumen, i.e. the lumen of the second fluid delivery means, as describedinfra. The outer diameter typically ranges from about 0.5 to 2.0. Theinner diameter of the partial occlusion catheter insert typically rangesfrom about 0.2 to 1.0, usually from about 0.25 to 1.0 and more usuallyfrom about 0.3 to 1.0 mm.

The above described partial and total catheter inserts are furthercharacterized by being capable of being attached at their proximal ends,either directly or through one or more attachment means, to a fluidreservoir, e.g. an acidic dissolution fluid reservoir and, in the caseof the partial occlusion catheter insert, a balloon inflation means. Arepresentation of a total occlusion catheter insert 30 according to thesubject invention is provided in FIG. 2B. A representative partialocclusion catheter insert is provided in FIG. 3. In FIG. 3, partialocclusion catheter insert 40 includes elongated tubular structure 42that is sealed at its distal end 48. Proximal to the distal end 48 isballoon 46, where the distance Y typically ranges from about 1 to 30 mm,usually from about 10 to 20 mm. Also depicted are infusion ports 44. Thediameter of the infusion ports may vary, but typically ranges from about0.2 to 1.2, usually from about 0.4 to 1.0 and more usually from about0.5 to 0.8 mm. Also shown is balloon inflation lumen 43, where theballoon inflation lumen has dimensions similar to those of ballooninflation lumen 23. As evidenced, the partial occlusion catheter insertincludes two lumens, a fluid introduction lumen and a balloon inflationlumen. Also visible in FIGS. 2B and 3 is second delivery means 35 whichincludes the second lumen, described in greater detail below.

The second lumen of the subject multi-lumen catheter devices is designedfor delivery of a pH elevating solution to the vascular site of thetarget occlusion. This lumen is generally present in a second fluiddelivery means (element 35 in FIGS. 2B and 3), where the fluid deliverymeans is generally an elongated tubular structure analogous to the firstfluid delivery means described supra. In the present coaxial embodiment,the dimensions of this second fluid delivery means, i.e. second catheterinsert, are such that the first fluid delivery means or catheter insertdescribed above (i.e. either the partial or total occlusion catheterinsert) can fit inside this second fluid delivery means, i.e. can fitinside the lumen of the second fluid delivery means. A furtherlimitation is that the first fluid delivery means must fit inside thesecond fluid delivery means in a manner such that an annular space isformed in the second lumen which is sufficient to convey the requisiteamount of pH elevating fluid to the vascular site during use of thedevice. As such, the inner diameter of the second lumen exceeds theouter diameter of the first fluid delivery means by at least about 0.6mm, sometimes at least about 0.9 mm and in certain embodiments at leastabout 1.2 mm. Accordingly, the inner diameter of the second fluiddelivery means ranges from about 0.8 to 2.5, usually from about 0.9 to1.9 and more usually from about 1.0 to 1.3 mm. The second fluid deliverymeans has an open distal end which, when positioned around the firstfluid delivery means during use, forms an annular opening through whichpH elevating fluid flows out of the second fluid delivery means and intothe vascular site during use. The total effective cross-sectional areaof the annular opening typically ranges from about 0.6 to 2.6, usuallyfrom about 0.8 to 1.9 and more usually from about 0.9 to 1.3 mm². Theoverall length of the second fluid delivery means typically ranges fromabout 90 to 210, usually from about 100 to 190 and more usually fromabout 110 to 150 cm. The second fluid delivery means is furthercharacterized by having a means for connecting to a pH elevating fluidreservoir, either directly or indirectly, at its proximal end.

The first and second lumens and their respective fluid delivery meansmay be combined into integrated catheters in certain embodiments. Anexample of a total occlusion catheter unit is presented in FIG. 12 whilean example of a partial occlusion catheter unit is presented in FIG. 13.

The third lumen in this coaxial embodiment of the subject devices is theoutermost lumen, which is generally present in an elongated tubularstructure analogous to the first and second fluid delivery means, asdescribed above. The third lumen present in this third fluid deliverymeans is employed to remove fluid from the vascular site. As such, thisthird fluid delivery means is properly viewed as an aspiration catheter.The aspiration catheter is generally an elongated tubular structurefabricated from a flexible, biologically acceptable material having aballoon or analogous vessel occlusion means positioned at its distalend. The length of the aspiration catheter may vary, but is generallyfrom about 80 to 200 cm, usually from about 90 to 180 cm and moreusually from about 100 to 140 cm. The outer diameter of the aspirationcatheter is selected so as to provide for access of the distal end ofthe catheter to the vascular site via the vascular system from theremote point of entry, where the outer diameter typically ranges fromabout 1.0 to 4.0 mm (3 to 12 Fr), usually from about 1.5 to 3.0 mm (4.5to 9.0 Fr) and more usually from about 1.7 to 2.7 mm (5 to 8 Fr). Theaspiration catheter is characterized by having an open distal end, wherethe inner diameter at the open distal end is sufficient to house thefirst and second coaxial fluid delivery means, as described supra, andremove fluid from the vascular site at the desired rate, e.g. a ratethat provides for substantially isometric or isobaric pressure in thevascular site during treatment, through the resultant annular space. Theinner diameter of the third or aspiration lumen, at least at its distalend and generally along the entire length of the aspiration catheter,typically ranges from about 0.2 to 2.0, usually from about 0.25 to 1.75and more usually from about 0.35 to 1.5 mm. The total effectivecross-sectional area at its distal end, i.e. the cross-sectional area ofthe annular space at the distal end opening, typically ranges from about1.3 to 3.9, usually from about 1.3 to 3.2 and more usually from about1.3 to 2.5 mm². Also present at the distal end of the aspirationcatheter is a vessel occlusion means, where the vessel occlusion meansis usually an inflatable balloon. The balloon is one that is inflatableto a volume sufficient to substantially occlude the vessel in which theaspiration catheter is positioned, e.g. by pressing against the intimalsurface of the vessel in which the aspiration catheter is positioned.The balloon is in fluid or gaseous communication with an inflation lumenthat runs the length of the aspiration catheter and can be connected toa balloon inflation means. The inflation lumen has an inner diameterthat typically ranges from about 0.1 to 0.5, usually from about 0.2 to0.4 mm. In certain embodiments, the aspiration catheter further includesa separate guidewire lumen. When present, the guidewire lumen has adiameter ranging from about 0.2 to 1.0 mm, usually from about 0.3 to 0.6mm. Thus, the aspiration catheter includes at least two distinct lumens,i.e. an aspiration lumen (also referred to herein as the third lumen)and a balloon inflation lumen, and in many embodiments includes threedistinct lumens, i.e. an aspiration lumen, a balloon inflation lumen anda guidewire lumen. A representation of an aspiration or irrigationcatheter is provided in FIG. 14.

The aspiration catheter is further characterized by being capable ofattaching, either directly or through one or more attachment means, atits proximal end to vacuum means, e.g. a negative pressure means, wheresuch means is sufficient to provide for the desired aspiration duringuse of the device, and a balloon inflation means, where such means issufficient to inflate the balloon at the distal end of the catheter whendesired.

A representation of the aspiration catheter of the subject cathetersystems found in the subject kits is provided in FIG. 2A. In FIG. 2A,aspiration catheter 20 includes elongated tubular member 22 and balloon24 located proximal to the distal end. The distance X between the distalmost portion of the balloon 24 and the distal end of the cathetertypically ranges from about 1 to 20, usually from about 5 to 10 mm. Alsoshown is distal open end 26 through which either the partial or totalocclusion insert catheter is moved and fluid is aspirated. Balloon 24 isinflatable via balloon inflation lumen 23.

Alternative Embodiments

In an alternative embodiments of the subject invention, at least two ofthe first, second and third lumens are not coaxial. In these alternativeembodiments, the configuration of the first, second and third lumens inthe device may vary greatly. For example, the first second and/or thirdlumens may be present on separate non-coaxial fluid delivery means. Assuch, the device could be made up of three different fluid deliverymeans bundled together to produce a triple lumen catheter device.Alternatively, a single fluid delivery means could house all threelumens. In certain embodiments, two of the lumens, i.e. the first andsecond lumen, will be present on a first fluid delivery means, whichfluid delivery means is coaxially positioned within the third lumen. Thefirst or internal fluid delivery means housing the first and secondlumens may take on a variety of configurations. In one configuration,the first and second lumens terminate or open at the distal end of theinternal fluid delivery means. In other configurations, one of thelumens opens at a different area from the other lumen. In theseembodiments, the first lumen typically opens at the distal end of theinternal fluid delivery means and the second lumen opens at a siteproximal to the distal end of the internal fluid delivery means. Thesecond lumen may open up at a one or more openings proximal to thedistal end of the internal fluid delivery means. In each of theseembodiments, the internal fluid delivery means housing the first andsecond lumens is present in a third lumen which is also housed by afluid delivery means, where this fluid delivery means may be referred toas an aspiration catheter, as described above.

Catheter Systems

As summarized above, the subject invention also provides cathetersystems suitable for use in the subject methods, as described in greaterdetail infra. By catheter system is meant two more disparate cathetercomponents which are capable of being assembled into a single unit, i.e.coaxial catheter assembly, having at least an inner catheter that isslidably positioned within the lumen of an outer catheter, i.e. acoaxial catheter assembly having an inner insert catheter that can bemoved relative to the outer catheter so as to produce varying distancesbetween the distal ends of the two coaxial catheters. For example, acatheter system which includes the above described coaxial embodimentswhere all three first, second and third lumens are coaxial, will includedisparate catheter fluid delivery means that fit within one another toproduce a coaxial triple lumen catheter as described above. In suchsystems, the system will at least include an aspiration catheter, a pHelevating fluid delivery catheter and at least one internal fluiddelivery catheter. In many systems according to this embodiment, thesystem will further include a second internal catheter, such that thefirst internal catheter is suitable for use in treating total occlusionsand the second internal catheter is suitable for use in treating partialocclusions. An exemplary catheter system of the subject inventionincludes the partial occlusion catheter unit, the total occlusioncatheter unit and the irrigation or aspiration catheter unit depicted inFIGS. 12 to 14.

Further Catheter Device and System Characteristics

The components of the subject catheter systems and catheter devices, asdescribed above, may be fabricated from any convenient material, withthe only limitation being that at least the inner surface of the firstlumen be fabricated from a material that withstands, i.e. does notdegrade upon contact with, the acidic dissolution fluid, at least forthe period of time during which the catheter system is used. Thematerials must also be able to withstand the effects of any reactionbyproducts produced by contact of the acidic dissolution solution withthe components of the target occlusion. Suitable materials includebiocompatible polymers, e.g. polyimide, PBAX, polyethylene, and thelike. Any glues or fittings that are employed must also be able to meetthe same criteria. Any convenient fabrication protocol may be employed,where numerous suitable protocols are known to those of skill in theart.

Methods

Also provided by the subject invention are methods of locallyintroducing active agents to vascular sites. In the broadest sense, thesubject catheter systems may be employed to introduce any active agentin a fluid delivery vehicle to a vascular site. The subject systemsachieve local delivery of active agents in fluid delivery vehicles byirrigating or flushing a portion of the vascular system with the fluidagent composition. Active agents of interest that may be locallyintroduced using the subject methods include: thrombolytic agents,growth factors, cytokines, nucleic acids (e.g. gene therapy agents),detergents and surfactants, and the like. Of particular interest is theuse of the subject catheter systems in the treatment of vascularcalcified occlusions, which application will now be described in greaterdetail as representative of the various methods in which the subjectcatheter systems may be introduced.

For treatment of vascular calcified occlusions with the subject catheterdevices and systems, the subject catheter systems are used to flush asurface of the target vascular occlusion with an acidic dissolutionfluid for a period of time sufficient for fluid flow to be to beenhanced through the vascular site. As indicated above, by enhanced ismeant that fluid flow is either established in situations where fluidflow is not initially present, e.g. where the target vascular occlusionis a total occlusion, or increased where some fluid flow through thevascular site is present, e.g. in situations where the vascular site isoccupied by a partial occlusion. The subject methods are furthercharacterized in that, simultaneously with the acidic dissolution fluid,a pH elevating fluid is also introduced into the vascular site of thetarget lesion, i.e. the target vascular site. A critical feature of thesubject methods is that the subject devices are used to introduce bothacidic dissolution fluid and pH elevating fluid to the target vascularsite in a manner such that the acidic dissolution fluid primarilycontacts the surface of the target occlusion, with the remainder of thetarget vascular site being contacted with fluid that has a pH which ismuch higher than that of the acidic dissolution fluid.

The Target Vascular Site

The target site through which fluid flow is enhanced by the subjectmethods is a site within a vessel, typically an artery or vein, andusually an artery. In many embodiments, the vascular site is aperipheral vascular site, by which is meant that the vessel in which thevascular site is located is a vessel found in one of the extremities ofthe patient to be treated, i.e. the arms or legs. Often, the vascularsite is a site in a lower extremity vessel, e.g. a lower extremityartery. As indicated above, of particular interest in certainembodiments are peripheral arterial vascular sites, where specificperipheral arteries of interest include: iliac arteries, femoropoplitealarteries, infrapopliteal arteries, femoral arteries, superficial femoralarteries, popliteal arteries, and the like. In yet other embodiments,the vascular site is present in a heart associated vessel, e.g. theaorta, a coronary artery or branch vessel thereof, etc. In yet otherembodiments, the vascular site is present in a carotid artery or abranch vessel thereof.

The vascular site is occupied by a vascular occlusion in such a mannerthat fluid flow through the vascular site, e.g. blood flow, is at leastimpeded if not substantially inhibited. By at least impeded is meantthat fluid flow is reduced by at least 20%, usually by at least 50% andmore usually by at least 80% through the vascular site as compared to acontrol. In such situations, the vascular site is occupied by a partialvascular calcified occlusion. By substantially inhibited is meant thatsubstantially no fluid flows through the vascular site. For purposes ofthis invention, fluid flow through a vascular site is considered to besubstantially inhibited where it is not possible to pass a guidewirethrough the vascular site, where the guidewire has a diameter rangingfrom 0.014 to 0.038 in and is applied to the site with a pressureranging from about 1 to 30 oz. A representation of a peripheral arteryhaving a vascular site occupied by a total vascular calcified occlusionis provided in FIG. 1A while a representation of a peripheral arteryhaving a vascular site occupied by a partial vascular calcifiedocclusion is provided in FIG. 1B. In FIGS. 1A & 1B, the external iliacartery 11 is shown as it branches into the SFA 12 and the profunda 13.Also shown are the medial circumflex and the later circumflex, 14 and 15respectively. The SFA is totally occluded by occlusion 16 in FIG. 1A andpartially occluded by occlusion 16 in FIG. 1B.

The Target Vascular Occlusion

The vascular occlusion that occupies the target vascular site isgenerally a calcified vascular occlusion, by which is meant that theocclusion includes at least some calcium containing component. Thecalcified occlusion may be a substantially pure mineral structure, ormay be a more complex formation that includes both mineral and othercomponents, including organic matter, e.g. lipids, proteins, and thelike. As mentioned above, the target vascular occlusion may be a partialor total vascular occlusion.

The mineral component making up the calcified lesion is generally madeup of one or more calcium phosphates, where the calcium phosphates aregenerally apatitic. The term “apatite” as used herein refers to a groupof phosphate minerals that includes ten mineral species and has thegeneral formula X₅(YO₄)₃Z, where X is usually Ca²⁺ or Pb³⁺, Y is P⁵⁺ orAs⁵⁺, and Z is F⁻, Cl⁻, or OH⁻. The term calcium apatite refers to agroup of phosphate minerals where X is Ca²⁺. The mineral component ofthe calcified occlusion typically includes one or more ofhydroxyapatite, carbonated hydroxyapatite (dahllite) and calciumdeficient hydroxyapatite.

In addition to the mineral component, the calcified occlusion thatoccupies the target vascular site may also comprise one or moreadditional components, where such components include: lipids;lipoproteins; proteins; including fibrinogen, collagen, elastin and thelike; proteoglycans, such as chondroitin sulfate, heparin sulfate,dermatans, etc.; and cells, including smooth muscle cells, epithelialcells, macrophages and lymphocytes. As such, calcified occlusions thatare targets of the subject methods include those that may be describedas: type IV, type V and type VI lesions, as defined in Stary et al.,Arterioscler. Thromb. Vasc. Biol. (1995)15:1512-1531.

In the vascular occlusions that occupy the target vascular sites of thesubject methods, the mineral component of the calcified occlusiongenerally makes up from about 10 to 100, usually from about 10 to 90 andmore usually from about 10 to 85 dry weight % of the occlusion. The sizeof the occlusion that is the target of the subject methods variesdepending on location and specific nature of the occlusion. Generally,the volume of the occlusion will range from about 20 to 10,000 mm²,usually from about 30 to 500 mm³ and more usually from about 50 to 300mm³.

In certain embodiments, one or both ends of the occlusion may becharacterized by being primarily thrombotic material, e.g. a thrombus,where the thrombotic domain of the occlusion extends for about 1 to 5cm. The nature of the thrombotic domain may be organized ordisorganized.

Contacting the Vascular Occlusion with an Acidic Dissolution Fluid

In the subject methods, one surface of the vascular occlusion, e.g. thedistal or proximal surface, is contacted with an acidic dissolutionfluid for a period of time sufficient for fluid flow to be establishedor enhanced through the vascular site. Contact with the vascular sitemay be accomplished in any convenient manner, so long as it results inthe enhancement of fluid flow through the vascular site. Generally, thesurface is dynamically contacted or flushed with the acidic dissolutionfluid.

By dynamic contact is meant that the fresh dissolution solution iscontacted with the surface of the target occlusion one or more times,including continuously, during the treatment period. In many preferredembodiments of the subject methods, the surface of the target occlusionis continuously contacted or flushed with the acidic dissolution fluid.In other words, the acidic dissolution fluid is introduced in a mannersuch that a continuous flow of the acidic dissolution fluid across thesurface of the occlusion is achieved.

Where the surface of the target occlusion is flushed with thedissolution fluid, it is preferred that the pressure in the localenvironment which includes the surface of the occlusion, i.e. the areabounded by the vessel walls, the surface of the target occlusion and thecatheter system used to deliver the solution, remains substantiallyisometric. By substantially isometric is meant that the pressure in thelocal environment does not vary by a significant amount, where theamount of variance over the treatment period does not vary by more thanabout 50%, usually by not more than about 10% and more usually by notmore than about 5%. In other words, the local environment remainssubstantially isobaric during the treatment period. Accordingly, wherefluid is dynamically contacted with the surface of the target occlusion,fluid is also simultaneously removed from the local environmentcomprising the surface of the target occlusion, such that the overallvolume of fluid in the local environment remains substantially constant,where any difference in volume at any two given times during thetreatment period does not exceed about 50%, and usually does not exceedabout 10%. As such, the dissolution fluid is introduced into the localenvironment of the target lesion in a manner such that the localenvironment remains substantially isovolumetric.

Where the acidic dissolution fluid is dynamically introduced into thevascular site, the dissolution fluid is introduced in a manner such thatthe flow rate of the dissolution solution through the vascular site ofthe lesion is generally at least about 10 cc/min, usually at least about20 cc/min and more usually at least about 60 cc/min, where the flow ratemay be as great as 120 cc/min or greater, but usually does not exceedabout 1000 cc/minute and more usually does not exceed about 500cc/minute, where by volume is meant the local environment of theocclusion, as defined above. The total amount of dissolution fluid thatis passed through the local environment of the lesion during thetreatment period typically ranges from about 100 to 1000 cc, usuallyfrom about 200 to 800 cc and more usually from about 400 to 500 cc. Thesolution is generally pressurized to achieve the desired flow rate, asdescribed supra. As such, the pressure at the distal end of the coaxialcatheter assembly through which the solution is introduced into thelocal environment typically ranges from about 50 to 1200 psi, usuallyfrom about 100 to 600 psi and more usually from about 200 to 400 psi. Itis important to note that the overall pressure in the local environmentis maintained at substantially isometric or isobaric conditions. Assuch, the negative pressure at the entrance to the aspiration catheter,e.g. the open annulus at the distal end of the aspiration catheter willbe of sufficient magnitude to provide for substantially isobaricconditions. Preferably, the overall pressure in the local environment ismaintained at a value ranging from about 0.1 to 3 psi, usually from about 0.5 to 2.5 psi and more usually from about 1 to 2 psi.

As indicated above, a critical feature of the subject methods is thatthe target vascular site is flushed with a pH elevating solutionconcomitantly or simultaneously with the acidic dissolution fluid in amanner sufficient such that only the surface of the target occlusion,and not the remainder of the target vascular site, is contacted with alow pH solution. By pH elevating solution is meant any solution that,upon combination with the acidic dissolution solution, produces asolution with an elevated pH with respect to the acidic dissolutionsolution. In principle, any fluid that, upon combination of with theacid dissolution fluid produces a solution having a pH higher than thatof the acidic dissolution fluid, may be employed, so long as the fluidis biocompatible, at least for the period of time that it is present inthe target vascular site. The pH elevating solution should have a pH ofat least about 4, usually at least about 6 and more usually at leastabout 8. As such, pH elevating fluids of interest include water,physiological acceptable buffer solutions, etc., where in manyembodiments, the pH elevating solution is a buffer solution.Representative buffer solutions of interest include: phosphate bufferedsaline, sodium bicarbonate and the like.

In the subject methods, the acidic dissolution and pH elevating fluidsare introduced into the vascular site in a manner such that only thetarget vascular lesion is contacted with the low pH acidic dissolutionfluid. As such, the remainder of the target vascular site is contactedwith a fluid that has a pH well above that of the acidic dissolutionfluid, where the lowest pH to which the remainder of the target vascularsite is subjected is not less than 4, preferably not less than 5 andmore preferably not less than 6. In other words, only the targetvascular occlusion is contacted with the low pH acid dissolution fluidwhile the remainder of the target vascular site is contacted with asolution the pH of which is not less than 4, preferably not less than 5and more preferable not less than 6. A representation of a targetvascular site being flushed with both an acidic dissolution fluid and apH elevating fluid according to the subject methods is provided in FIGS.4, 6 and 11.

In FIG. 4, where the target lesion is a partial occlusion, a coaxialpartial occlusion catheter device, as described above, is introducedinto the vascular site such that the balloon 46 of the partial occlusioninsert 40 and the balloon 24 of the aspiration catheter 20 flank thepartial occlusion 34. Acidic dissolution fluid is introduced by theplurality of ports 44 on the partial occlusion insert. A pH elevatingsolution is concomitantly introduced through annular space 45. Fluid isthen removed from the vascular site by the aspiration catheter 20through annular space 26. FIG. 6 provides a view of a total occlusioncatheter insert flushing a vascular site 12 of a total occlusion 17. Ascan be seen in FIG. 6, acidic dissolution fluid is introduced throughthe central catheter and pH elevating solution is introduce via thecatheter immediately concentric with the center catheter. Fluid isremoved from the vascular site via the aspiration catheter, in which thecentral and intermediate catheters are coaxially positioned. FIG. 11provides a representation of the pH gradients which occur in thevascular site during treatment according to the present invention. Thedarkest area represents the lowest pH. The grey area represents thehighest pH, where the pH of this area is not lower than 4, usually notlower than 5 and preferably no lower than 6.

Time Period

The surface of the target occlusion is contacted, e.g. flushed, with theacidic dissolution fluid for a period of time sufficient for fluid flowto be enhanced or established through the vascular site, e.g.established or improved. As such, where the target occlusion is a totalocclusion, contact is maintained for a period of time sufficient for aguidewire to be passed through the vascular site, as described above.Alternatively, where the target occlusion is a partial occlusion,contact is achieved for a period of time sufficient for the rate offluid flow to be increased through the vascular site, generally by atleast about 10%, usually by at least about 50%, and in many embodimentsby at least about 100%. Generally, the period of time during which thesurface of the occlusion is contacted with the acidic dissolutionsolution ranges from about 5 to 100 minutes, usually from about 10 to 30minutes. Where contact is achieved by flushing the target occlusion withthe acidic dissolution solution, the contact duration typically lastsfor a period of time ranging from about 5 to 30 minutes, usually fromabout 10 to 30 minutes and more usually from about 10 to 20 minutes.

Acidic Dissolution Solutions

A variety of different types of acidic dissolution solutions may beemployed in the subject methods. The acidic treatment solutions thatfind use in the subject methods generally have a pH of less than about6.5, where the pH is usually less than about 4.0 and more usually lessthan about 3.0. In many preferred embodiments, the pH ranges from 0 to2, and usually 0 to 1. The acidic treatment solution can include anumber of different types of acids, where the acids may or may notinclude a hydrocarbon moiety, i.e. a hydrogen bonded directly to acarbon atom. Suitable acids that lack a hydrocarbon moiety includehalogen acids, oxy acids and mixtures thereof, where specific acids ofinterest of this type include, but are not limited to, hydrochloric,nitric, sulfuric, phosphoric, hydroboric, hydrobromic, carbonic andhydroiotic acids. For such acids, the acid can be a concentrated acid,or can be diluted. Upon dilution, the concentration of an inorganic acidwill generally be from about 10 N to about 0.01 N, preferably between 5N to 0.1 N. Also of interest are acids that include a hydrocarbonmoiety, where such acids include, but are not limited to, any organicacid of one to six (C₁ to C₆) carbons in length. Organic acids of thistype include, but are not limited to, formic, acetic, propionic, maleic,butanoic, valeric, hexanoic, phenolic, cyclopentanecarboxylic, benzoic,and the like. For an organic acid, the acid can be in concentrated form,or can be diluted. The acidic treatment solution can be composed ofeither a monobasic or a polybasic acid. Acids are “monobasic” when theyhave only one replaceable hydrogen atom and yield only one series ofsalts (e.g., HCl). Acids are “polybasic” when they contain two or morehydrogen atoms which may be neutralized by alkalies and replaced byorganic radicals.

In many embodiments of the subject invention, the acid solution ishypertonic, by which is meant that the osmolarity of the solution isgreater than that of whole blood, i.e. the osomolarity is greater than300 mosmol. The solution may be rendered hypertonic by including anyconvenient component or components in the solution which provide for thedesired elevated osmolarity.

Any convenient agent that is capable of increasing the osmolarity of thesolution may be employed, where suitable agents include salts, sugars,and the like. In many embodiments, the agent that is employed to renderthe solution hypertonic is one or more, usually no more than three, andmore usually no more than two, different salts. Generally, the saltconcentration in these embodiments of the solution is at least about 100mosmol, usually at least about 200 mosmol and more usually at leastabout 300 mosmol, where the concentration may be as high as 3000 mosmolor higher, depending on the particular salt being employed to render thesolution hypertonic, where the solution may be saturated with respect tothe salt in certain embodiments. Salts that may be present in thesubject solutions include: NaCl, MgCl₂, Ringers, etc. where NaCl ispreferred in many embodiments.

Of particular interest in many embodiments is the use of a hydrogenchloride solution. In hydrogen chloride solutions that find use in thesubject invention, the concentration of HCl in the solution ranges fromabout 0.001 to 1.0 N, usually from about 0.01 to 1.0 N and more usuallyfrom about 0.1 to 1.0 N. In many embodiments, the hydrogen chloridesolution will further include one or more salts which make the solutionhypertonic, as described above. In certain preferred embodiments, thesalt is NaCl, where the concentration of NaCl in the solution is atleast 0.05 M, usually at least 0.10 M, and more usually at least 0.15 M,where the concentration may be as high as 0.25 M or higher. In certainembodiments, the solution will be saturated with NaCl.

Of particular interest are aqueous hydrogen chloride solutions thatconsist of water, hydrogen chloride and NaCl. The concentration ofhydrogen chloride in these solutions of particular interest ranges fromabout 0.01 to 1.0 N, usually from about 0.05 to 0.5 N and more usuallyfrom about 0.075 to 0.25 N. The concentration of NaCl in these solutionsof particular interest ranges from about 0.05 to 0.25 M, usually fromabout 0.05 to 0.10 M.

Further Embodiments of the Subject Methods

In a number of embodiments of the subject methods, the methods in whichthe surface of the target occlusion is contacted with an acidicdissolution fluid may be modified to include a number of additionalmethod steps. Additional method steps that may be present in the overallprocess include: rendering the local environment of the target occlusionbloodless, contacting the target occlusion with a solution designed toremove organic components, washing or rinsing the local environment ofthe target occlusion, applying external energy to the target occlusion;imaging the target vascular site; establishing or expanding a passagewaythrough an initial thrombotic domain of the target occlusion; and thelike.

Rendering the Local Environment Bloodless In many preferred embodiments,as described above, the local environment of the target occlusion isrendered substantially bloodless prior to introduction of the acidicdissolution fluid. In these embodiments, the balloon(s) of the assembledcatheter system is inflated to physically isolate the local environmentfrom the remainder of the circulatory system and then the localenvironment is flushed with a physiologically acceptable solution, suchthat substantially all of the blood present in the solution is removed.Typically, a washing solution will be employed in this step of renderingthe local environment bloodless. Examples of washing solutions that mayfind use in these embodiments include: water for injection, salinesolutions, e.g. Ringer's, phosphate buffered saline, or otherphysiologically acceptable solutions. The washing solution includes ananticlotting factor in many embodiments, where anticlotting factors ofinterest include heparin and the like. The washing solution can alsocontain chelating agents.

Use of Organic Structure Dissolution Solutions

As mentioned above, in addition to the acidic dissolution solution,certain embodiments of the subject invention include a step ofcontacting the target occlusion with a dissolution solution which servesto remove at least a portion of the non-mineral, typically organic,phase of the target occlusion. The nature of this ‘organic phasedissolution solution’ varies depending on the nature of the targetocclusion. Representative active agents that may be present in thisorganic phase dissolution solution include: oxidizing agents; organicsolvents; lipid dissolving agents such as surfactants, e.g. TWEEN™, anddetergents, where ionic detergents are of particular interest, e.g.cholic acid, glycocholic acid, benzylkonium chloride; enzymes, and thelike.

Application of External Energy

In certain embodiments, external energy is applied to the vascular siteto promote mechanical break-up of the occlusion into particles or debristhat can be easily removed from the vascular site. Any means of applyingexternal energy to the vascular site may be employed. As such, jets orother such means on a catheter device which are capable of providingvarying external forces to the occlusion sufficient to cause theocclusion to break up or disrupt may be employed. Of particular interestin many embodiments is the use of ultrasound. The ultrasound can beapplied during the entire time of contact of the cardiovascular tissuewith the acidic treatment solution, or the ultrasound can be applied foronly part of the treatment period. In one embodiment, ultrasound isapplied for several short periods of time while the dissolutiontreatment solution is contacted with the target occlusion. There areseveral devices for the application of ultrasound to cardiovasculartissue known to those of skill in the art. See e.g. U.S. Pat. No.4,808,153 and U.S. Pat. No. 5,432,663, the disclosures of which areherein incorporated by reference.

In such methods where external energy is applied to the occlusion inorder to disrupt or break-up the occlusion into particles or debris, theparticles or debris may range in size from about 0.01 to 4.0 mm, usuallyfrom about 0.1 to 2.0 mm and more usually from about 0.5 to 1.0 mm. Insuch instances, the method may further include a step in which theresultant particles are removed from the vascular site. Particles may beremoved from the vascular site using any convenient means, such as thecatheter of the subject invention described in greater detail infra.

Another means that may be employed to apply external energy to thelesion during the dissolution process is to use a mechanical means ofapplying external energy. Mechanical means of interest include movingstructures, e.g. rotating wires, guidewires, which physically contactthe target occlusion and thereby apply physical external energy to thetarget lesion. See e.g. FIGS. 9 and 10.

Imaging

In addition, it may be convenient to monitor or visualize the vascularsite prior to or during treatment. A variety of suitable monitoringmeans are known to those of skill in the art. Any convenient means ofinvasive or noninvasive detection and/or quantification may be employed.Such means include plain film roentgenography, coronary arteriography,fluoroscopy, including digital subtraction fluoroscopy,cinefluorography, conventional, helical and electron beam computedtomography, intravascular ultrasound (IVUS), magnetic resonance imaging,transthoracic and transesophageal echocardiography, rapid CT scanning,antioscopy and the like. Any of these means can be used to monitor thevascular site before, during or after contact with the dissolutionfluid.

In many embodiments, an imaging agent is employed, where the imagingagent may or may not be present in the acidic dissolution solution.Imaging agents of particular interest include: non-ionic imaging agents,e.g. CONRAY™, OXILAN™, and the like.

Thrombus Removal Step

The subject methods may further include a thrombus removal step, e.g.where the calcified domain of the target occlusion is covered by athrombotic domain, as described above. In such methods, any thrombusremoval means that is capable of providing sufficient access of theacidic dissolution solution to the surface the calcified domain of thetarget lesion may be employed. Thus, where the thrombotic domain is adisorganized domain, it may be sufficient to pass increasingly largerdiameter guidewires through the domain until a passageway of sufficientwidth to provide access of the catheter assembly described above to thesurface of the occlusion is established. Alternatively, portions of thethrombotic domain may be removed, e.g. via atherectomy methods,angioplasty methods, and the like, where devices for performing suchprocedures are known to those of skill in the art. See the patentreferences cited in the Relevant Literature section, supra, whichreferences are herein incorporated by reference.

Use of a Plurality of Solutions

In many embodiments, the subject methods include contacting the surfaceof the target occlusion with a plurality, i.e. two or more, distinctsolutions, one of which is an acidic dissolution solution. Where one ormore additional distinct solutions, such as priming solutions, washingsolutions, organic phase dissolution solutions and the like areemployed, as described below, such disparate solutions are generallyintroduced sequentially to the vascular site. For example, the targetocclusion may be contacted with the following order of solutions: (1)washing solution to render the local environment substantiallybloodless; (2) organic phase dissolution solution, e.g. detergentsolution such as cholic acid solution, to remove organic phases from thetarget lesion; (3) acidic dissolution solution to demineralize thetarget occlusion; and (4) washing solution. Other sequences of solutionapplication can also be employed. See U.S. patent application Ser. No.09/353,127, the disclosure of which is herein incorporated by reference.Generally, in any method where a plurality of different solutions arecontacted with the target occlusion, a pH elevating solution isintroduced simultaneously with at least the acidic dissolution solution,as described above.

Outcome

As discussed above, the subject methods result in the enhancement offluid flow through the vascular site occupied by the occlusion. Fluidflow is considered to be enhanced in those situations where the vascularsite is totally occluded when a guide wire can be moved through thevascular site without significant resistance. Fluid flow is consideredto be enhanced in those situations in which the vascular site ispartially occluded when the rate of fluid flow through the vascular siteincreases by at least 10%, usually by at least 50% and in manyembodiments by at least 100%.

In certain embodiments, the subject methods will not result in completeremoval of the target occlusion from the vascular site. As such, thevascular site, while not totally occluded, may still include lesiondeposits on the wall which impede fluid flow through the vascular siteand the removal or reduction of which is desired. Any convenientprotocol for treating these remaining deposits may be employed, e.g.balloon angioplasty, atherectomy, stenting, etc. Also of interest is theuse of two balloon catheters and an acidic dissolution solution, asdescribed in PCT/US99/15918, the disclosure of which is hereinincorporated by reference.

Of particular interest in those embodiments where the vascular site isinitially totally occluded, fluid flow through the total occlusion isfirst established using the catheter assembly made up of the totalocclusion catheter insert inside the aspiration catheter. Followingestablishment of fluid flow, the rate of fluid flow is increased usingthe catheter assembly made up of the partial occlusion catheter insertinside the aspiration catheter.

Additional Applications

In addition to methods of enhancing fluid flow through a target vascularsite, methods and devices are also provided for reducing the mineralcontent of non-intimal tissue, as described in copending applicationSer. No. 09/382,571, the disclosure of which is herein incorporated byreference. Specifically, the subject invention provides methods anddevices that are analogous to those disclosed in the copendingapplication, with the only difference being that the target tissue iscontacted simultaneously with both the acidic dissolution solution and apH elevating solution. As such, the devices are modified such that ameans for introducing a pH elevating solution at the same time as theacidic dissolution solution to the target tissue is provided.

Systems

Also provided by the subject invention are systems for practicing thesubject methods, i.e. for enhancing fluid flow through a vascular siteoccupied by a vascular occlusion. The subject systems at least includethe catheter systems as described above, a manifold, a fluid reservoirfor storing acidic dissolution fluid, a fluid reservoir for storing a pHelevating fluid and a negative pressure means for providing aspirationor suction during use of the system. The systems may further include anumber of optional components, e.g. guidewires, pumps for pressurizingthe dissolution fluid, and the like. See e.g. U.S. patent applicationSer. No. 09/384,860, the disclosure of which is herein incorporated byreference.

A representative system is provided in FIG. 5. In FIG. 5, system 50 ischaracterized by having catheter device 51 in fluid communication withthe various fluid and vacuum sources require to practice the methods asdescribed above. Specifically, the outer aspiration catheter 52 of thecatheter device 51 is in communication with a medical grad vacuumregulator and vacuum means 53 by aspiration line 53A. The central orirrigation catheter 54 of the catheter device 51 is in fluidcommunication with power injector source of acidic dissolution solution,55. The intermediate catheter of the catheter device 51 is in fluidcommunication with a source of pH elevating solution 56, e.g. PBS/Hep.Finally, syringe 57 is used to inflate the balloon of the catheterdevice via the balloon inflation line 58.

Utility

The subject devices and methods find use in a variety of differentapplications in which it is desired to enhance fluid flow, usually bloodflow, (or at least pass a guidewire through), a vascular site that isoccupied by a calcified vascular occlusion, e.g. a partial or totalocclusion. As such, the subject methods and devices find use in thetreatment of peripheral vascular disease, etc. The subject methods alsofind use in the treatment of coronary vascular diseases. By treatment ismeant that a guidewire can at least be passed through the vascular siteunder conditions which, prior to treatment, it could not. Treatment alsoincludes situations where the subject methods provide for larger fluidpassageways through the vascular site, including those situations wherefluid flow is returned to substantially the normal rate through thevascular site. The subject methods may be used in conjunction with othermethods, including balloon angioplasty, atherectomy, and the like, aspart of a total treatment protocol.

A variety of hosts are treatable according to the subject methods.Generally such hosts are “mammals” or “mammalian,” where these terms areused broadly to describe organisms which are within the class mammalia,including the orders carnivore (e.g., dogs and cats), rodentia (e.g.,mice, guinea pigs, and rats), lagomorpha (e.g. rabbits) and primates(e.g., humans, chimpanzees, and monkeys). In many embodiments, the hostswill be humans.

Kits

Also provided by the subject invention are kits for use in enhancingfluid flow through a vascular site occupied by an occlusion. The subjectkits at least include a catheter device or system, as described above.The kits may further include one or more additional components andaccessories for use with the subject catheter systems, including tubingfor connecting the various catheter components with fluid reservoirs,syringes, pumping means, etc., connectors, one or more guidewires,dilators, vacuum regulators, etc.

In certain embodiments, the kits further include one or more solutions,or precursors thereof, where in such embodiments the kits at leastinclude an acidic dissolution fluid, such as a hydrochloric acidsolution, as described above, where the solution may be present in acontainer(s), e.g. a flexible bag, a rigid bottle, etc. For kits thatare to be used in methodologies in which the fluid is flushed throughthe local environment of the lesion, the amount of dissolution fluidpresent in the kit ranges from about 0.5 to 500 liters, usually fromabout 0.5 to 200 liters and more usually from about 0.5 to 100 liters.In many embodiments, the amount of dissolution fluid in the kit rangesfrom 0.5 to 5 liters, usually from about 0.5 to 2.0 liters and moreusually from about 0.5 to 1.5 liters. Alternatively, the kit maycomprise precursors of the dissolution solution for use in preparing thesolution at the time of use. For example, the precursors may be providedin dry form for mixing with a fluid, e.g. water, at the time of use. Inaddition to the dissolution fluid or precursors thereof, the kit mayfurther comprise one or more additional fluids (or dry precursorsthereof), such as a priming solution, a washing solution, contrastmedium, and the like. In many embodiments, the kits further include atleast a pH elevating solution, e.g. a buffer solution such as phosphatebuffered saline.

Other elements that may be present in the subject kits include variouscomponents of the systems, including manifolds, balloon inflation means,e.g. syringes, pumping means, negative pressure means etc.

Finally, the kits include instructions for practicing the subjectmethods, where such instructions may be present on one or more of thekit components, the kit packaging and/or a kit package insert.

The following examples are offered by way of illustration and not by wayof limitation.

Experimental

I. A 50 Year Old Male Having a Total Occlusion in the SuperficialFemoral is Treated as Follows.

1. The patient is heparinized using standard procedures.

2. An introducer sheath is placed either in the same leg to provideretrograde access or in the opposite leg to provide cross-over access.

3. A guidewire is inserted and advanced to the site of the totalocclusion.

4. The catheter device is inserted so that the distal end of the deviceis at the vascular site occupied by the total occlusion. The balloon isthen inflated by depressing the syringe, such that the balloon occludesthe vessel proximal to the occlusion. See FIG. 6.

5. Contrast medium is then injected into the vascular site to confirmthe location of the distal end of the catheter and the inflated balloon.

6. A sufficient amount of heparinized phosphate buffered saline is theninjected through port into the isolated vascular site or localenvironment and aspirated therefrom such that the isolated localenvironment is rendered substantially bloodless.

7. The surface of the total occlusion is then flushed with both anacidic dissolution fluid A (0.1N HCl, 0.05 M NaCl) and a phosphatebuffered saline solution at the same time as shown in FIG. 6.

8. As the occlusion is demineralized, the catheter insert is advancedindependent of the aspiration catheter and buffer catheter.

9. Where desired, the balloon may be deflated, the entire devicerepositioned, and then balloon may be reinflated to move the distal endof the total occlusion catheter insert to a site further into theocclusion. See FIGS. 7 and 8.

10. Once a passage through the occlusion sufficient to pass a guidewirethrough the occlusion is produced, the device is removed.

11. The above procedure results in fluid flow through the vascular siteoccupied by the lesion being reestablished, as evidenced by passing aguidewire through the vascular site.

12. Where desired, following reestablishment of fluid flow through thetotal occlusion, the total occlusion catheter insert is removed. Aguidewire is then inserted through the large lumen of aspirationcatheter 20 to a space beyond the distal end of the occlusion. A partialocclusion catheter insert is then introduced over the guidewire to aposition such that the balloon at the distal end of the insert is on thefar side of the partial occlusion. The vascular site is then flushed asshown in FIG. 4 until the desired amount of lesion dissolution isachieved.

II. Variations on the Above Procedure

The above procedure is performed with the additional step of applyingmechanical energy to the occlusion during flushing with the acidicdissolution solution. FIG. 9 shows mechanical energy being applied tothe occlusion by contacting a guidewire 91 with the surface of the totalocclusion during flushing. FIG. 10 shows mechanical energy being appliedto the surface of the occlusion with the proximal end of the totalocclusion insert. Other means of applying external energy, e.g.mechanical energy, may also be employed.

It is evident from the above discussion and results that improvedmethods of enhancing blood flow through a vascular occlusion areprovided. Specifically, the subject invention provides a means forreadily establishing fluid flow through a vascular site totally occludedby a calcified vascular occlusion, which has heretofore been difficultto practice. As such, the subject invention provides a means for usingless traumatic procedures for treating peripheral vascular disease,thereby delaying or removing the need for graft procedures and/oramputation. A critical feature of the subject devices and methods isthat only the target occlusion is subjected to the low pH conditions ofthe acidic dissolution solution. As such, unwanted contact of otherportions of the target vascular site and/or host are avoided. As such,the subject invention represents a significant contribution to thefield.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

What is claimed is:
 1. A catheter device comprising: a first lumen inside of a first fluid delivery member that is open at its distal end andis in fluid communication with an acidic solution source; a second lumeninside of a second fluid delivery member that is open at its distal endand is in fluid communication with a buffer solution source; and a thirdlumen inside of an aspiration member that is open at its distal end,wherein said aspiration member includes a vascular occlusion means atits distal end; wherein said first, second and third lumens are coaxialand said first delivery member is movable relative to said second andthird lumens.
 2. The catheter device according to claim 1, wherein saidsecond delivery member is moveable relative to said third lumen.
 3. Acatheter device comprising: (a) an inner first tubular member that isopen at its distal end and is in fluid communication with an acidicsolution source; (b) a middle second tubular member, wherein said secondtubular member is open at its distal end and is in fluid communicationwith a buffer solution source; and (c) a third outer tubular memberhaving a first vascular occlusion means, wherein said third tubularmember is an aspiration member and is open at its distal end; whereinsaid tubular members are coaxial and are movable relative to each other,and further wherein each of said tubular members; (i) has a proximal anddistal end; and (ii) comprises a lumen.
 4. A catheter system comprising:(a) an aspiration catheter comprising an elongated tube having anaspiration lumen ending in an open distal end and art inflatable balloonat said distal end; and (b) a second elongated tube coaxially positionedinside of said aspiration catheter, wherein said second elongated tubeis open at its distal end and is in fluid communication with a buffersolution source; and (c) both of: (i) a total occlusion catheter insertcomprising an elongated tube having an open distal end; and (ii) apartial occlusion catheter insert consisting essentially of an elongatedtube having a sealed distal end, an inflatable balloon at said distalend, and at least one infusion port proximal to said inflatable balloon;wherein said catheter inserts are in communication with an acidicsolution source; and wherein at least said total and partial occlusioncatheter inserts are capable of being slidably positioned within saidsecond elongated tube to produce an annular space at the distal end ofsaid elongated tube through which fluid may flow.
 5. The catheter systemaccording to claim 4, wherein said aspiration catheter is in fluidcommunication with a negative pressure source.
 6. A system for enhancingfluid flow through a vascular site occupied by a vascular occlusion,said system comprising: (a) a catheter device according to claim 1; (b)a manifold; (c) an acidic fluid dissolution reservoir in fluidcommunication with said first lumen; (d) a buffer solution reservoir influid communication with said second lumen; and (e) a source of negativepressure in fluid communication with said third lumen.
 7. The systemaccording to claim 6, wherein said system further includes a ballooninflation means.
 8. The system according to claim 2, wherein saidballoon inflation means is a syringe.
 9. The system according to claim6, wherein said system further comprises a guidewire.
 10. A kit for usein enhancing fluid flow through a vascular site occupied by a vascularocclusion, said kit comprising: a catheter device according to claim 1;art acidic dissolution solution; and a buffer solution.
 11. The kitaccording to claim 10, wherein said kit comprises the system accordingto claim
 4. 12. The kit according to claim 10, wherein said kit furthera guidewire.
 13. The kit according to claim 10, wherein said kit furthercomprises an imaging agent.